Persistent viral infections represent a significant public health problem with hundreds of millions of people infected. However, therapies that enable the host to purge these infections have been unsuccessful due to a limited understanding of the cellular and molecular mechanisms that promote virus persistence. Over the last decade studies have demonstrated that persistent viruses take advantage of negative immune regulatory molecules (IL-10, PD-1) to suppress the antiviral CD4 and CD8 T cell responses, resulting in T cell exhaustion, enabling virus persistence. Deletion of several immune stimulatory molecules such as IL-6 and IL- 21 result in lifelong virus persistence, suggest that the balance between negative and positive immune regulators determines virus clearance or persistence. Importantly, molecules such as IL-6 and IL-21 have known T follicular helper cell (TFH) and B cell stimulatory capacities and depletion of these molecules in vivo results in reduced TFH, B cell responses and antibody production. In fact, studies in humans have demonstrated that although TFH and germinal center (GC) B cells are generated during human persistent virus infection, their function is impaired. Despite the above findings, the mechanisms that restrain/promote optimal TFH, B and antibody responses during persistent virus infection are incompletely understood. We recently made the unexpected finding that during persistent LCMV infection IFN-I signaling was essential to promoting (rather than preventing) virus persistence. Importantly, IFN-I signaling supported induction of negative immune regulators (NIR) IL-10 and PD-L1, immune suppression, T cell exhaustion and lymphoid tissue destruction. Following up our published studies we now report that blockade of IFN-I signaling results in enhanced TFH, GC and plasma B cell responses. Thus we hypothesize IFN-I signaling restrains antiviral humoral immunity during persistent virus infection. The ultimate goal of this proposal is to generate a detailed understanding how IFN-I signaling modulates immune responses during persistent virus infection. The output of our studies should be a detailed cellular and molecular understanding how IFN-I regulates anti-viral humoral and cellular immune responses during persistent virus infection. In this project will use anti-IFNAR1 neutralizing antibodies, genetic and biochemical tools to determine how IFNAR1 signaling regulates TFH, GC and plasma B cell responses during a model persistent virus infection. This proposal encompasses important basic and potentially translational research goals - 1) to understand the mechanisms by which IFNAR1 signaling suppresses immune cell function; 2) discover IFN-I regulated cellular and biochemical pathways that promote virus persistence; and 3) leverage this knowledge to instruct future development of therapeutic modalities to promote immune responses to control of human persistent viral infection.